N-amylsulfamyl benzoic acids



Patented Aug. 26, 1952 N-AMYLSULFAMYL BENZOIG ACIDS James M. Sprague, Drexel Hill, Pa., assignor to Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No Drawing.

Original application August 20,

1949, Serial No. 111,584. Divided and this application June 3, 1950, Serial No. 166,084

2 Claims.

This invention relates to a sulfamylbenzoic acid which is effective as an adjuvant for use in conjunction with the administration of penicillin to provide an increase in the blood plasma penicillin concentration with a given dose of penicillin, thereby making possible very high penicillin blood levels, or permitting the use of smaller quantities of penicillin foriprovidingj a given blood level, or permitting the less frequent administration of penicillin while maintaining a penicillin blood level adequate for bactericidal or bacteriostatic purposes. The invention also relates to the preparation of various dosage forms in which this new compound is incorporated for administration by various routes.

Penicillin today is a well established therapeutic agent used in the treatment of bacterial, in particular, coccus infections, For internal use, it is commonly administered intravenously, or intramuscularly, or orally. Where high blood levels are required intravenous administration or administration by continuous venoclysis, is used.

The major cause of. the difficulties involved in attempting to maintain adequate or high penicillin blood levels follows from the fact that substantially all of the penicillin in the blood is removed in a single circulation through the kidneys. J

Penicillin appears to be almost quantitatively excreted from the hood by the epithelial cells of the tubules, at least within plasma concentrations which have been explored, with the result that its rate of excretion from the blood stream is approximately five timesthat of materials which are excreted by glomerular filtration alone, the tubular excretion accounting for about 80 (81) and the glomeruli about (19) Various proposals have been made to overcome the difficulties due to the rapid elimination of pencillin, such as the administration of it in suspension in an oleaginous material, the mixture being administered by intramuscular injection. While this proposal is effective in prolonging the time interval between injections, its disadvantage is that the penicillin is still excreted almost quantitatively when the blood passes through the renal system, and therefore does not permit the maintenance of high blood levels nor does it permit the use of smaller quantities of penicillin to obtain a given blood level.

The second proposal which has been made to provide for the reduction in the rate of exretion of penicillin has been to main conjunction with it, a material which, like penicillin, is selectively excreted by the tubules. By having the'ratio of the added agent to the penicillin suiiiciently large,

this concept provides for a substantial, reduction in the rate of excretion of penicillin by the tubules and. thus slows down its removal to a substantial extent. Various agents including diodrast and hippuric acid, or derivatives or precursors thereof, have been proposed or used for this purpose. Such agents do not, however, seem to afford a solution to the problem of value except in extreme cases, because as the reduction in the rate of penicillin excretion is a reflection of the degree of overloading of the tubuleswith materials which they function to remove from thelblood, it is necessary to maintain a very high concentration of the agent in the blood stream to afford a favorable partition ratio between the agent and the penicillin and, in addition, because the agents are themselves rapidly removed from the blood stream, it is necessary to administer them in large quantities to maintain the necessary high plasma concentrations. This presents an additional problem since inorder to maintain the high concentration of these agents they must be administered intravenously as they are not well absorbed from the gastro-intestinal tract.

The present invention is based upon the discovery that removal of penicillin from theblood stream by the kidney tubules can be effectively blocked by the-new adjuvant of this invention, 1 (para-carboxyphenylsulfonamido) n-pentane, another name for it being para-(n-amylsulfamyD-benzoic acid, having the general formula n-amyl the blood stream. The adjuvant itself is not excreted to any substantial extent by the tubules, and the availableevidence indicates that on coming into contact with the epithelial cells of the tubules, it operates to block their action by interference with the normal functioning of the epithelial cells and does not inhibit the excretion of the penicillin by competing with it within the tubular functional capacity. Thus, the adiuvant is effective in eliminating or very radically reducing tubular excretion ofpenicillin in plasma concentrations around 10 mg. per 00., which is about the threshold value for agents such as p-amino-hippuric acid or diodrast which inhibit tubular penicillin excretion by competition for the available tubular excretion capacity. The highly eiiective adjuvant of this invention will reduce the excretion of penicillin by the tubules, at a blood plasma concentration of about mg. per 100 cc. to almost Zero, so that the actual elimination of penicillin from the blood stream becomes substantially that resulting from glomerular filtration, that is, about one-fifth the normal rate (ignoring plasma binding). The adjuvant itself is eliminated by the ,glomeruli.

The adjuvant may be administered orally or, when dissolved in an aqueous solution, it may be administered intravenously or intramuscular-1y. This last method has not yet proven desirable for single injection of the material, because in general, administration of more than 2 cc. per single injection intramuscularly is inadvisable, and the quantities of adjuvant desirable to use, i. e., 4 to 16' grams per day, are such as to make injection by this route impractical. However, amyl-sulfamylbenzoic acid or its salts is 'well adapted for continuous intramuscular or subcutaneous clysis.

In general, oral administration of the adjuvant at the rate of 4 to 1.6 grams per day is adequate to suppress the rate of penicillin excretion to an extent such that the blood level with a given dose of penicillin administered orally or intramuscularly in aqueous solution will be increased to as .much as four times the level obtained without the use of the adjuvant, and will permit either the use of a very much smaller quantityof penicillin to provide a'given blood level, for example, permitting the penicillin doses to be about one- .fourth of those commonly used, .or permitting the 'pmvision of penicillin blood levels several times as great as those obtainable with the administration of penicillin by the routes ordinarily used today.

The adjuvant of the invention or a suitable salt of it may be administered in admixture with the penicillin, or separately therefrom. .In any event, whether the adjuvant is administered in admixture with or separately from the penicillin, the quantity used should be such as to provide a concentration in the blood stream of adjuvant adequate to block substantially the excretory mechanism of the tubules. Maximum efiect will be obtained with blood plasma concentrations of about 5 to mg. per v100 cc., obtainable at dosage levels of about etc 16 grams per dayorally and somewhat less thanthis intravenously.

The adjuvant may be prepared in any convenient dosage form, either alone or admixed with penicillin, such as in a compressed tablet, a dry filled capsule or a soft elastic capsule. It is to be understood, of course, that other ingredients, such as binders, diluents, excipients, antacid substances, or other inert or therapeutically active compounds may be incorporated into any selected dosage form along with the adjuvant or adjuvant plus penicillin, provided the added ingredient does not destroy the activity of either the adjuvant or penicillin. Similarly, the adjuvant and, if desired, the penicillin may be dispersed in an oleaginous base either alone or along with other suitable substances and filled into soft elastic capsules or an aqueous solution may be prepared and filled into ampuls. Other suitable dosage forms will be readily apparent to those skilled in the art, and it is not the purpose of this discussion to limit the mode of packaging or administration to those specifically described herein.

The new sulfamyl benzoic acid of the invention is generally made by first preparaing a para- 1 para- (ii-amylsulfamyl) 4 carboxybenzenesulfonyl halide by oxidation of para-toluenesulfonyl halide, or by preparing para-cyanobenzenesulfonyl halide by treating para-sulfamyl benzoic acid with phosphorus pentachloride. The para-carboxybenzenesulfonyl halide or para-cyanobenzenesulfonyl halide thus formed is reacted with the mono-namylamine, advantageously using an excess, for example, two to three equivalents, of the amine, and when the cyanobenzenesulfonyl halide reactant is used, hydrolyzing the product thus formed "to the corresponding carboxyl derivative. The reaction is preferably carried out in the presence of a solvent, such as acetone or pyridine and the like, or in aqueous sodium hydroxide, and preferably with cooling. Any by product formed during the reaction is removed by treating the reaction medium with a Weak, alkaline substance, such as an aqueous sodium bicarbonate solution, filtering oil the precipitated by-product, and then recovering the amylsul'iamvl benzoic acid from the filtrate by'acidificaition.

The preparation of the new compound of the invention is illustrated by, but not restricted to the following example:

Emmp'le I.1 p-carbo:ryphenylsulfonamidoenpentane.-15.F7 g. of i-carboxybenzenesulfonylchloride were added in portions with stirring to a chilled solution of 18.27 g. of n-amylamine in 200 cc. reagent acetone. The mixture was concentrated to'about 40 cc. on a steam bath and diluted with cold water. The oil that separated was worked thoroughly with dilute hydrochloric acid and the resulting brown solid filtered. The product was dissolved in excess aqueous sodium bicarbonate ,anda small insoluble residue filtered and discarded. After precipitation withacid the product, l-pcarboxyphenylsulfonamido n-pentane, was recrystallized from alcohol after treating with charcoal.

The invention is further illustrated by, but not restricted .to', the following various dosage forms of different compositions for administration by variousroutes.

Example .a.-Compr'essed tablet-40,000 grams of lactose and 100,000 grams of the adjuvant,

-.benzoic acid, are uniformly mixed and wetted with sufiicient water tov permit its ready granulation. 2,000 grams of dried cornstarch, 500 grams of .karaya gum powder, 2,500 grams of talc, and 1,000 grams oi calcium steara-te are intimately mixed and then mixed together uniformly'with the 110,000 grams of the mixture of the granulated adjuvant and lactose. The final mixture is then tableted (using inch die standard curvature punches) yielding 200,000 tablets of 0.58'gram each, and each containing 0.5 gram of the adjuvant.

Measured amounts of the composition of Example a or merely the adjuvant alone can be filled into hard gelatine, telescopic capsules, each holding 0.5 gram of adjuvant.

Alternately, the adjuvant may be homogeneously dispersed in an equal quantity of corn oil, and the composition encapsulated in known manner in soft, elastic sheet gelatin, hermetically sealed capsules each containing one gram of the adjuvant-oilcomposition.

Emamplcb.-.AmpuZ.-l0 kilos of the adjuvant, para- (n-amylsulfamyl) -benzoic acid, are suspended in very nearly 50 liters of distilled water and ,1431 grams of sodium hydroxide are added and distilled water added to make the volume of solution up to 50 liters (pl-I is about 7.4). The solution is then filled into ampuls for cc. liquid content each, which are then flame-sealed and autoclaved at pounds pressure for minutes.

Example c.-.-Compressecl tablet containing penicillin;-l0,000 grams of lactose are mixed with. 100,000 grams of the adjuvant, para-(namylsulfamyD-benzoic acid, and granulated as in Example a. 3375 grams of sodium penicillin (1630 units per mg), 2625 grams dried cornstarch, 500 grams karaya gum powder, 2500 grams talc and. 1000 grams calcium stearate are mixed together in an atmosphere controlled at 10% relative humidity at 21 C., and then under the same conditions mixed with the granulation of the adjuvant and the lactose and tableted with the same die as in Example a yielding 200,000 tablets weighing 0.6 gram and each containing 0.5 gram of adjuvant and 25,000 units penicillin (plus 10% excess).

Example d.--Dry filled capsule with penicillin-Under atmosphere controlled as in Example 0, 25 kilos of the adjuvant, para-(n-amylsulfamyl) -benzoic acid, 850 grams of crystalline penicillin sodium (as used above), and 150 grams of dried cornstarch are intimately and uniformly mixed and the mixture filled into capsules, yielding 50,000 capsules, each holding 0.52 gram of mixture containing 0.5 gram of adjuvant and 25,000 units penicillin (plus 10% excess).

Example e.--Soft elastic capsule with penicillin.Under atmosphere controlled as in Example c, 1.69 kilos of the same crystalline penicillin sodium are homogeneously dispersed in 48.31 kilos of corn oil and 50 kilos of the adjuvant, para-(n-amylsulfamyl)-benzoic acid, similarly dispersed in the oil, and the resulting composition encapsulated in known manner in soft, e1astic, sheet gelatin, hermetically sealed capsules, yielding 100,000 capsules, each holding one gram net of the composition and containing 0.5 gram of adjuvant with 25,000 units penicillin (plus 10% excess).

Example f.-Flame-sealed ampul filled with penicillin-12.5 kilos of the adjuvant, para-(namylsulfamyl) -benzoic acid, are stirred into very nearly liters of sterile, pyrogen-free, distilled water and 1831 grams of sodium hydroxide are added to aid in the dissolution of the adjuvant. Then 390 grams of monopotassium phosphate are added and, under atmospheric conditions as in Example 0, 169 grams of the same crystalline penicillin sodium are added and stirred into solution and sufficient water added to bring the total volume of solution to 30 liters. 12 cc. of this solution are then filled into each of the required number of 20 cc. total volume ampulvials. The contents of the vials are then quickly frozen by rotating them in a bath of methyl Cellosolve chilled with Dry-Ice to 70 0., and desiccated under high vacuum for 48 hours by the method and apparatus as in United States Patent No. 2,353,985, and rubber stoppers inserted in the neck of each of the containers while the vacuum is still being maintained. The vacuum is then broken and the containers removed from the apparatus and the extension of the glass neck beyond the top of the stoppers is flame-sealed. The contents of the flame-sealed ampul-vial is then restored with sterile, pyrogenfree, distilled water shortly before the product is to be used. When thus restored to 20 cc. liquid volume, the resulting solution is buffered at pl-I 7.4: and contains 100,000unitS penicillin (plus 7 the 10% excess): and. 25% offthe adjuvant.)

Example g;-Ampul oil suspension with penicillin-3 kilos of USP-white wax are mixed into 35.127 kilos of purified peanut oilheated sufficiently to melt and permit homogeneous disper sion of the white wax. While this mixture is still suiiiciently liquid, and under atmospheric conditionsas in Examplec, 10 kilos :of the ad.- juvant, para (n-arnylsulfamyl) -benzoic acid,

and 1873 gramsof 1 c,alcium,-;penicillin (734 units/mg.) are added andthe mixture stirred to homogeneity; Each cc. of the resulting oil suspension contains 25,000 units of penicillin (plus 10% excess) and 0.2 grams of adjuvant. It is put up in flame-sealed, ampulscontaining suitable volume of the suspension which is asstablc as the ordinary penicillin in peanut oil preparations.

In those compositions containing penicillin, it it advisable, in accordance with customary practice, to include an excess of the penicillin, for example, a ten per cent excess over the labellclaimed quantity in accordance with present practice. An excess of penicillin introduces no difficulty save its cost. The penicillin used may be any of the forms available for use, such as the calcium, sodium, potassium, procaine, and the like salts of amorphous or crystalline penicillin.

The quantity per dose of adjuvant and penicillin will depend upon the blood level and duration of action required for the particular condition encountered in each case. An advantageous ratio of adjuvant to penicillin per tablet or capsule is about one-half gram of the selected adjuvant to 25,000 to 200,000 units of penicillin.

The compositions of the invention may also include an antacid material, such as aluminum hydroxide, magnesium trisilicate, trisodium citrate, calcium carbonate, magnesium oxide, or other antacid substances suitable for administration for the purpose of neutralizing gastric acidity. The amount of antacid material is limited only to that which is desirable to use in connection with penicillin or which can be physically incorporated in a tablet or capsule of suitable size for administration.

As to binders and lubricants used in making the tablets, such materials as lactose, corn-starch, gum karaya, talc. calcium stearate, gelatin, ethyl cellulose, mineral oil, propylene glycol, glycerin, and the like, may be included in proportions commonly used in preparing tablets of this nature.

If the compositions are produced in the form of suspensions or solutions in an oleaginous material, there are available various substances which may be used for this purpose. Corn oil or other suitable oil is used with advantage.

This application is a division of U. S. patent application Serial No. 111,584, filed August 20, 1949, by myself and Charles S. Miller, now abandoned, which in turn was in part a continuation of the then co-pending U. S. patent application Serial No. 695,040, filed September 5, 1946, by myself and Karl H. Beyer, Jr., now abandoned.

Having now particularly described the invention, what is claimed is:

1. An adjuvant which is a member of the group consisting of para (n amylsulfamyl) benzoic acid having the formula:

n-amyl and its non-toxic, water-soluble salts.

H r and :its non-toxic, water-soluble salts, the quantity of adjuvant and penicillin in the composition being in'the ratio of 0.5 gram of 'adjuvan-t to from 25,000 to 200,000 units of penicillin.

, JAMES M. SPRAGUE.

REFERENCE S v CIT-ED The following references are of record in the file of this patent;

(8 UNITED STATES PA'IENTS Number Name Date 2,162,211 Andersen June '13, 1939 OTHER REFERENCES Pratt et al., Antibiotics, Lippincott Company,

1949, pages 112 to 116 Reid, Prolongaftion Penicillinaseelnhibiting Compounds,

,Exptl. Biol. and Med 443.

Soc-H00,

. (Book .in Division 43;)

of Penicillin Activity with Proc. Soc.

., Nov. 1946, pages 4138 to Activity of Penicillin Combined with other Anti-Streptococcal Agents, Archives Biochemistry, Sept. 1944, Meads, Caronamid Med. Assoc, Nov. 20, 1

pages 99 to 106. e and Penicillin, J. Am, 948, pages 874 to 877. 

2. A COMPOSITION SUITABLE FOR THERAPEUTIC USE, COMPRISING PENICILLIN AND AN ADJUVANT WHICH IS A MEMBER OF THE GROUP CONSISTING OF PARA-(NAMYLSULFAMYL)-BENZOIC ACID HAVING THE FORMULA: 